CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

for astrogliosis, by RT-qPCR, (iii) glutamate uptake capacity by a fluorometric assay, (iv) chemokines and proinflammatory cytokines secretion and gene expression by astrocytes using ELISA and RT-qPCR respectively, (v) modulation of neutrophil transmigration across an in vitro BBB model. Results: Our results show that JQ1 and bryostatin-1 reduce yeast phagocytosis. Moreover, those two LRA decrease the speed and quantity of Aβ uptake by astrocytes compared to an untreated control. Bryostatin-1 also increases C3 expression and disturbs the astrocytic glutamate uptake/release balance. Moreover, bryostatin-1 increases secretion of chemokines and proinflammatory cytokines CCL2, IL-6, IL-8 and GM-CSF by astrocytes. In contrast, JQ1 represses their production. Lastly, we observed that neutrophil transmigration across our BBB model is increased in response to bryostatin-1, and that this LRA induces neutrophil extracellular traps formation. Conclusion: Taken together, our results suggest that bryostatin-1 and JQ1 could induce Aβ aggregation and senile plaque formation involved in Alzheimer’s disease progression. Moreover, bryostatin-1 could lead to excitotoxicity by disrupting glutamate homeostasis. Chemokines and proinflammatory cytokines secreted by astrocytes in response to bryostatin-1 could induce an inflammatory syndrome and favor neutrophil invasion in the CNS that could lead to neurological disorders. Our study provides evidence that the safety of the shock and kill approach needs to be further investigated in the brain compartment. 455 EFAVIRENZ PHARMACOKINETICS IN HIV/TB COINFECTED PERSONS RECEIVING RIFAPENTINE Anthony Podany 1 , Erin Sizemore 2 , Michael Chen 2 , Neil A. Martinson 3 , Rodney Dawson 4 , Sharlaa Badal-Faesen 5 , Sachiko Miyahara 6 , Ekaterina Kurbatova 2 , William C. Whitworth 2 , Richard E. Chaisson 7 , Susan E. Dorman 7 , Payam Nahid 8 , Kelly Dooley 7 , Susan Swindells 1 1 University of Nebraska, Omaha, NE, USA, 2 CDC, Atlanta, GA, USA, 3 Perinatal HIV Research Unit, Soweto, South Africa, 4 University of Cape Town, Cape Town, South Africa, 5 Wits Reproductive Health and HIV Institute, Johannesburg, South Africa, 6 Harvard University, Cambridge, MA, USA, 7 The Johns Hopkins University, Baltimore, MD, USA, 8 University of California San Francisco, San Francisco, CA, USA Background: AIDS Clinical Trials Group Study A5349/Tuberculosis Trials Consortium Study 31 (S31) is a phase III trial comparing two short-course TB treatment regimens containing high dose daily rifapentine (RPT) to standard TB treatment. RPT is a known CYP inducer and efavirenz (EFV) is a CYP substrate; thus, there is a potential risk of decreased EFV exposure and consequently increased risk of virologic failure. The pharmacokinetics (PK) of this combination have not been evaluated. An objective of S31 was to evaluate the effect of RPT on EFV PK, initially among a subset of participants on stable EFV-containing antiretroviral therapy (ART) at the time of initiation of RPT-containing TB treatment. Methods: This substudy included participants already suppressed on at least two months of EFV-containing (600mg) ART, and randomized to one of two regimens containing daily RPT (1200mg), isoniazid (H), pyrazinamide, and either ethambutol or moxifloxacin. Mid interval EFV concentrations were measured in plasma samples collected at weeks 0 (pre-RPT/H), 4, and 8 during concomitant RPT/H. EFV apparent oral clearance (CL/F) was modeled using Bayesian estimation; population PK priors were taken from previous EFV PK studies. Week 4 and 8 EFV concentrations were combined to estimate EFV CL/F during RPT/H therapy. The geometric mean ratio (GMR) and 90% confidence interval (CI) of the pre and during RPT/H EFV CL/F values were calculated. The protocol specified that >80% of participants should have EFV concentrations ≥1 mg/L for enrollment to continue. Results: Of 23 evaluable participants, 52%were female, 91% Black/African, and median age was 37 years (25-53). All 23 had HIV-1 RNA <200 copies/mL at randomization, 16/16 (100%) had HIV-1 RNA <200 copies/mL at week 8; the median baseline CD4+ count was 401 cells/mm 3 (118-998). The GMR for EFV CL/F was 0.88 (0.75-0.96). The number of participants with EFV concentrations ≥ 1 mg/L at both week 4 and 8, was 21 (91%). Median (IQR) RPT concentrations were 14.7 mg/L (12.2-19.25 mg/L). Conclusion: The CL/F of EFV decreased slightly with RPT/H. However, the proportion of participants with EFV concentrations ≥1mg/L did not cross below the pre-specified threshold of 80%. Plasma HIV-RNA levels during RPT/H indicated maintenance of viral suppression. These data provide preliminary

support for co-administration of high-dose RPT/H with EFV-containing ART. Evaluation of EFV PK in participants starting ART after initiation of study RPT- containing TB treatment is underway.

456 EFAVIRENZ PHARMACOKINETICS WITH RIFAMPIN DOUBLE DOSE IN TB-HIV INFECTED PATIENTS Daniel W. Atwine 1 , Elisabeth Baudin 2 , Thibaut Gelé 3 , Winnie R. Muyindike 4 , Mworozi Kenneth 1 , Racheal Kyohairwe 1 , Kenneth Kananura 1 , Dan Nyehangane 1 , Patrick Orikiriza 1 , Valérie Furlan 3 , Anne-Marie Taburet 5 , Aurélie Barrail-Tran 6 , Maryline Bonnet 7 1 Epicentre, Mbarara, Uganda, 2 Epicentre, Paris, France, 3 Hôpital Bicêtre, Le Kremlin- Bicetre, France, 4 Mbarara University of Science and Technology, Mbarara, Uganda, 5 INSERM, Le Kremlin-Bicetre, France, 6 University of Paris-Sud, Orsay, France, 7 IRD, Montpellier, France Background: There is increasing interest towards a potential reduction of tuberculosis (TB) treatment duration with use of high-dose rifampicin (R) among HIV-negative patients. Little is known among HIV-positive patients on antiretroviral therapy (ART). The ANRS 12292 Rifavirenz phase 2 trial evaluated efavirenz (EFV) pharmacokinetics (PK) in Ugandan HIV/TB co-infected patients receiving high-dose R (20 mg/kg) as part of their standard TB treatment for the first 2 months. Methods: Newly diagnosed, confirmed pulmonary TB, ART-naïve, adults were randomized to 3- regimens administered QD. All patients were started on TB treatment and initiated on ART 2-4 weeks after. They received isoniazid(H)/ pyrazinamide(Z)/ethambutol(E) and tenofovirDF/lamivudine at standard dosing during the first 8 weeks with R20mg/kg and EFV600mg (group G1); R20mg/ kg and EFV 800mg (G2); R10mg/kg and EFV600mg (Control C). At 8 weeks of follow-up, all patients were switched to standard R and EFV doses. Drug intake was observed. Blood samples were drawn 4 weeks after EFV initiation and 4 weeks after R discontinuation. EFV plasma concentrations were assayed by validated High Performance Liquid Chromatography assay. PK parameters were estimated by a model-independent method. The 90% confidence interval (CI) of the geometric mean ratios (GMR) of PK parameters with and without TB treatment was compared to the predefined 0.70-1.43 range for concentrations to remain within the therapeutic window. Plasma HIV-viral load (VL) was monitored 4, 12 and 24-26 weeks after ART initiation and mycobacterial sputum culture (Mycobacteria Growth Indicator Tube) 8 weeks after starting TB treatment. Results: Of 97 included patients (G1 31; G2 33; C 33), 87 were evaluable for PK. Median age, weight and CD4 count were 33 years, 53.6 kg and 141 cells/µL, respectively and 77%were males. EFV PK parameters are summarized in the table below. TB culture conversion was 85.7% (G1), 86.7% (G2) and 80.0% (C). At 12 weeks post-ART initiation, 92.6%, 86.2% and 92.6% of patients had VL < 400 copies/mL, respectively. No relationship could be evidenced between VL decline and EFV concentrations. During the first 8 weeks, 6 (2 per arm) and 4 (G1=1; G2=2; C=1) patients had alanine aminotransferase increase > grade 3 and neuropsychiatric events > grade 2, respectively. Conclusion: Despite a trend to lower EFV concentrations when R dosing was doubled, concentration remained in the therapeutic window and there was no sign of decreased tolerance.

Poster Abstracts

CROI 2018 162